The Lens Research Laboratory is comprised of two teams of researchers, one headed by Dr. Frank Lovicu in the Dept. of Anatomy & Histology, Anderson Stuart Building on the main University campus and the other headed by Prof. John McAvoy at the Save Sight Institute, Sydney Eye Hospital on Macquarie Street.
The work of the Lens Research Laboratory is primarily directed at identifying the molecules and mechanisms that govern the behaviour of cells of the ocular lens, in health, ageing and disease. Our studies have identified a number of molecules that play key roles in both normal and pathological lens development and growth. Currently we are working to gain a better understanding of how these molecules are regulated in the eye. This is fundamental to identifying new therapeutics for retarding or preventing cataract, one of the most common and costly diseases of ageing.
The lens transmits and focuses light onto the retina. To do this it needs to be transparent and to have appropriate refractive properties. This depends on the development and maintenance of a highly ordered cellular architecture. The lens consists of two forms of cells encapsulated within a basement membrane; (i) elongated fibre cells, grow to several millimetres in length, and are precisely aligned to form a regularly packed spheroidal mass, and (ii) cuboidal epithelial cells form a single-layered sheet that covers the anterior surface of the fibres. Whilst the fibre cells make up the bulk of the lens and mostly determine its optical properties, epithelial cells play a key role in maintaining an appropriate physiological environment within the lens. In addition, the epithelium contains the ‘stem cells’ that proliferate, migrate and differentiate into the new fibres that are progressively added to the fibre mass throughout life. We have focussed our attention on growth factors because of their importance in regulating cell fates in many diverse developmental systems. Using a unique lens epithelial explant culture system we have identified members of the FGF growth factor family as inducers of lens cell proliferation, migration & differentiation; responses that are induced in a progressive dose-dependent manner. We have proposed that an anterior-posterior gradient of FGF in the eye determines lens polarity and growth patterns and testing this hypothesis continues to be a major area of research activity in our laboratory. In addition to FGF, we are actively exploring the differential mitogenic effects of other growth factors primarily as a means of identifying which of these is important for regulating lens cell proliferation in the eye. Our more recent studies have also identified molecules, including members of the Wnt and Frizzled gene families, as well as putative growth factor antagonists, that appear to be essential for maintenance of the lens epithelium, primarily serving to tightly regulate its structural and functional characteristics.
In addition to better understanding normal lens developmental biology, our growth factor studies have also helped us to gain insights into the molecular basis of the major lens pathology, cataract. We have shown that members of the transforming growth factor beta (TGFß) family induce aberrant growth and differentiation of lens cells. This progressively leads to disruption of normal cellular architecture and opacification of the lens. Cataract is the most common cause of blindness in the world today. Although surgery is generally effective, in many countries it cannot keep pace with the growing demand. Moreover, complications such as aberrant growth and differentiation of lens cells left behind after cataract surgery (most commonly referred to as posterior capsule opacification), require further treatment and add to the cost of cataract management. Because of its clinical significance it is vital to understand how TGFß induces cataractous effects on the lens and most importantly how it is regulated in the eye. This information is fundamental to understanding the molecular basis of cataract and devising strategies for prevention.
Some of the projects currently under investigation in the laboratory include:
Normal Lens Biology
• Investigate and characterize the signalling pathways downstream of different growth factors to determine how they influence lens cell proliferation and/or fibre differentiation.
• Use lens epithelial explant cultures to identify specific factors that maintain the normal lens epithelial phenotypic characteristics including cell-cell and cell-matrix adhesion and communication.
• Investigate the role of signalling by members of the TGFß super-family during lens development. Further studies are being undertaken to examine the role of other TGFß family members (eg. BMPs) in lens development.
• Using lens epithelial explants and the characterisation of transgenic mice to determine the role of novel lens-specific genes (growth factor antagonists) thought to be involved in regulation of growth factor bioavailability.
Lens Pathology (Cataract)
• Using transgenic mouse models to further understand how TGFß induces and regulates cataract formation.
• Using lens epithelial explant cultures to determine how TGFß disrupts the normal lens signalling pathways and induces an epithelial-mesenchymal transition characteristic of cataract.
• Using electron microscopy and immunolabelling techniques to characterise the initiation and progression of cataract formation in mutant mouse models.
Development of the Ocular Lens
Edited by Frank J. Lovicu, Michael L. Robinson
Published November 2004
Development of the Ocular Lens provides a current view of research in lens developmental biology, emphasising recent technical and molecular breakthroughs. Elucidation of the mechanisms that govern lens development has enabled us to understand how the normal lens forms and how developmental processes, namely cell proliferation and differentiation, are involved in the maintenance of its normal structure, function and growth throughout life. This knowledge is fundamental to our understanding of many lens disorders. The ocular lens has also become a model for understanding the developmental biology of more complex organ systems. In this book, leading experts in lens cell biology and development discuss lens evolution, induction, morphology, the regulation of the lens cell cycle and fiber cell differentiation, as well as lens regeneration. This book is a broad and authoritative treatment of the subject that will serve as a reference for graduate students and research scientists in developmental biology and in the visual sciences, as well as for ophthalmologists.
Chamberlain CG, McAvoy JW. Induction of lens fibre differentiation by acidic and basic fibroblast growth factor (FGF). Growth Factors 1989;1:125-134.
Lovicu FJ, McAvoy JW. Structural analysis of lens epithelial explants induced to differentiate into fibres by fibroblast growth factor (FGF). Exp Eye Res. 1989;49:479-494.
McAvoy JW, Chamberlain CG. Fibroblast growth factor (FGF) induces different responses in lens epithelial cells depending on its concentration. Development 1989;107:221-228.
Parmigiani CM, McAvoy JW. A morphometric analysis of the development of the rat lens capsule. Curr Eye Res. 1989;8:1271-1277.
Richardson NA, McAvoy JW. An enzyme-linked immunosorbent assay for the quantitation of DNA. J Immunol Meth. 1989;125:287-289.
McAvoy JW, Chamberlain CG. Growth factors in the eye. Prog Growth Factor Res. 1990;2:29-43.
Richardson NA, McAvoy JW. Age-related changes in fibre differentiation of rat lens epithelial explants exposed to fibroblast growth factor. Exp Eye Res. 1990;50:203-211.
Chamberlain CG, McAvoy JW, Richardson NA. The effects of insulin and basic fibroblast growth factor on fibre differentiation in rat lens epithelial explants. Growth Factors 1991;4:183-188.
Parmigiani CM, McAvoy JW. The roles of laminin and fibronectin in the development of the lens capsule. Curr Eye Res. 1991;10:501-511.
McAvoy JW, Chamberlain CG, de Iongh RU, Richardson NA, Lovicu FJ. The role of fibroblast growth factor in eye lens development. Ann NY Acad Sci. 1991; 638:256-274.
McAvoy JW, Chamberlain CG, Richardson NA, Lovicu FJ. Fibroblast growth factor, a lens-inducing molecule from the retina In 'New Frontiers in Ophthalmology'. Editor CY Khoo Elsevier Science Publishers, Amsterdam 1991; 627-631.
de Iongh R, McAvoy JW. Distribution of acidic and basic fibroblast growth factors (FGF) in the foetal rat eye: implications for lens development. Growth Factors 1992;6:159-177.
Richardson NR, McAvoy JW, Chamberlain CG. Age of rats affects response of lens epithelial explants to fibroblast growth factor. Exp Eye Res. 1992;55:649-656.
Lovicu FJ, McAvoy JW. Age of rats affects response of lens epithelial explants to FGF: an ultrastructural study. Invest Ophthalmol Vis Sci. 1992;33:2269-2278.
Hales AM, Chamberlain CG, McAvoy JW. Measurement of lens cell migration on a laminum substratum using image analysis. J Comput Assist Microsc. 1992; 4:135-139.
Peek R, McAvoy JW, Lubsen NH, Schoenmakers JGG. Rise and fall of crystallin gene messenger levels during fibroblast growth factor induced terminal differentiation of lens cells. Dev Biol. 1992; 152:152-160.
de Iongh RU, McAvoy JW. Cellular localisation of aFGF during early lens development by a triple fluorescent labelling technique. J Comput Assist Microsc. 1993; 5:31-36.
Lovicu FJ, McAvoy JW. A structural analysis of fibroblast growth factor (FGF)-induced lens fibre differentiation in vitro. J Comput Assist Microsc. 1993; 5:57-63.
Schulz MW, Chamberlain CG, de Iongh RU, McAvoy JW. Acidic and basic FGF in ocular media and lens: implications for lens polarity and growth patterns. Development 1993;118:117-126.
Lovicu FJ, McAvoy JW. Localisation of aFGF, bFGF and HSPG in rat lens: implications for lens polarity and growth patterns. Invest Ophthalmol Vis Sci. 1993; 34:3355-3365.
Richardson NA, Chamberlain CG, McAvoy JW. IGF-I enhancement of FGF-induced lens fibre differentiation in rats of different ages. Invest Ophthalmol Vis Sci. 1993; 34:3303-3312.
de Iongh RU, McAvoy JW. Spatio-temporal distribution of acidic and basic FGF indicates a role for FGF in lens morphogenesis. Develop Dynam 1993; 198:190-202.
Liu J, Hales AM, Chamberlain CG, McAvoy JW. Induction of cataract-like changes in rat lens epithelial explants by transforming growth factor-ß. Invest Ophthalmol Vis Sci. 1994; 35: 388-401.
Chamberlain CG, Hales AM, Liu J, McAvoy JW. TGF-ß induced cataract-like changes in lens epithelia. Letter to the Editor. Invest Ophthalmol Vis Sci. 1994; 35:3787-3788.
Hales AM, Schulz MW, Chamberlain CG, McAvoy JW. TGF-ß1 induces lens cells to accumulate _-smooth muscle actin, a marker for subcapsular cataracts. Curr Eye Res. 1994; 13:885-890.
Lovicu FJ, Chamberlain CG, McAvoy JW. Differential effects of aqueous and vitreous on fiber differentiation and extracellular matrix accumulation in lens epithelial explants. Invest Ophthalmol Vis Sci. 1995; 36:1459-1469.
Hales AM, Chamberlain CG, McAvoy JW. Cataract induction in lenses cultured with transforming growth factor-ß. Invest Ophthalmol Vis Sci. 1995; 36:1709-1713.
Schulz MW, Chamberlain CG, McAvoy JW. Inhibition of TGFß-induced cataractous changes in lens explants by ocular media and _2-macroblobulin. Invest Ophthalmol Vis Sci. 1996; 37:1509-1519.
de Iongh RU, Lovicu FJ, Hanneken A, Baird A, McAvoy JW. FGF receptor-1 (flg) expression is correlated with fibre differentiation during rat lens morphogenesis and growth. Develop Dynam 1996; 206:412-426.
Sussman MA, McAvoy JW, Rudisill M, Swanson B, Lyons GE, Kedes L, Blanks J. Lens tropomodulin: developmental expression during differentiation. Exp Eye Res. 1996; 63:223-232.
Liu J, Chamberlain CG, McAvoy JW. IGF enhancement of IGF-induced fiber differentiation and DNA synthesis in lens explants. Exp Eye Res. 1996; 63:621-629.
Hales AM, Chamberlain CG, Murphy CR, McAvoy JW. Estrogen protects lenses against cataract induced by TGFß. J Exp Med. 1997;185:273-280.
Schulz MW, Chamberlain CG, McAvoy JW. Binding of FGF-1 and FGF-2 to heparan sulphate proteoglycans of the mammalian lens capsule. Growth Factors 1997;14:1-13.
Chamberlain CG, McAvoy JW. Fibre differentiation and polarity in the mammalian lens: A key role for FGF. Prog Ret Eye Res. 1997;16:443-478.
Lovicu FJ, de Iongh RU, McAvoy JW Expression of FGF-1 and FGF-2 mRNA during lens morphogenesis, differentiation and growth. Curr Eye Res. 1997;16:222-230.
Wang DZM, Hammond VE, Abud HE, Bertoncello I, McAvoy JW, Bowtell DDL. Genetic interaction between Sos1 and weak EGF receptor mutations demonstrates a requirement for Sos1 in growth factor signalling and a strategy for analysing mammalian signalling proteins. Genes Develop 1997;11:309-320.
de Iongh RU, Lovicu FJ, Chamberlain CG, McAvoy JW. Differential expression of FGF receptors during rat lens morphogenesis and growth. Invest Ophthalmol Vis Sci. 1997;38:1688-1699.
Lovicu FJ, Overbeek PA. 1998. Overlapping effects of different members of the FGF family on lens fiber differentiation in transgenic mice. Development. 125: 3365-3377.
Srinivasan, Y., Lovicu FJ, Overbeek PA. 1998. Lens-specific expression of Transforming Growth Factor ß1 in Transgenic Mice Causes Anterior Subcapsular Cataracts. J Clin Invest. 101: 625-634.
Gordon -Thomson C, de Iongh RU, Hales AM, Chamberlain CG, McAvoy JW. Differential cataractogenic potency of TGF-ß1, TGF-ß2 and TGF-ß3 and their expression in the postnatal rat eye. Invest Ophthalmol Vis Sci. 1998;39:1399-1409.
Klok EJ, Chamberlain CG, Lubsen NH, McAvoy JW. Induction and maintenance of differentiation of rat lens epithelium by FGF-2, insulin and IGF-I. Exp Eye Res. 1998;67:425-431.
Shang F, Gong X, McAvoy JW, Chamberlain C Nowell Jr TR, Taylor A. Ubiquitin-dependent pathway is up-regulated in differentiating lens cells. Exp Eye Res. 1999;68:179-192.
Lovicu FJ McAvoy JW. Spatial and temporal expression of p57KIP2 during murine lens development. Mech Develop. 1999; 86:65-69.
McAvoy JW, Chamberlain CG, de Iongh RU, Hales AM, Lovicu FJ. Lens development, Eye. 1999;13:425-437.
Hales AM, Chamberlain CG, Dreher B, McAvoy JW. Intravitreal injection of TGFß induces cataract in rats. Invest Ophthalmol Vis Sci. 1999;40:3231-3236.
Lovicu FJ, Kao W-K, Overbeek PA. 1999. Ectopic gland induction by lens-specific expression of keratinocyte growth factor (FGF-7) in transgenic mice. Mech Develop. 88:43-53
Adams DJ, van der Weyden L, Kovacic A, Lovicu FJ, Copeland NG, Gilbert DJ, Jenkins NA, Ioannou PA and Morris BJ. 2000. Chromosomal localization and characterization of the mouse human zinc finger protein 265 gene. Cytogenet Cell Genet. 88:68-73.
Hales AM, Chamberlain CG, McAvoy JW. Susceptibility to TGFß-induced cataract increases with ageing in the rat. Invest Ophthalmol Vis Sci. 2000;41:3544-3551.
Ueda Y, Chamberlain CG, Satoh K McAvoy JW. Inhibition of FGF-induced _A-crystallin promoter activity in lens epithelial explants by TGFß. Invest Ophthalmol Vis Sci. 2000;41:1833-1839.
Lovicu FJ, Kolle G, Yamada T, Little MH, McAvoy JW. Ocular expression of Crim1 during murine development. Mech Develop. 2000;94:261-5.
McAvoy JW, Chamberlain CG, de Iongh RU, Hales AM, Lovicu FJ. Peter Bishop Lecture: growth factors in lens development and cataract: key roles for FGF and TGFß. Clin Exp Ophthalmol. 2000;28:133-139.
Saika S, Okada Y,Miyamoto T, Oshnishi Y, Ooshima A, McAvoy JW. Smad translocation and growth supression in lens epithelial cells by endogenous TGFß. Exp Eye Res. 2001;72:679-686.
de Iongh RU, Gordon-Thomson C, Hales AM, Chamberlain CG, McAvoy JW. TGF-ß receptor expression in the lens: implications for differentiation and cataractogenesis. Exp Eye Res. 2001;72:649-659
de Iongh, RU., Lovicu, FJ, Overbeek, P. A., Schneider, MD., Joya, J., Hardeman, E. and McAvoy, JW. (2001). Requirement for TGFß receptor signaling during terminal lens fiber differentiation. Development. 128:3995-4010.
Zhao S, Hung F-C, Colvin J. S, White, A., Dai, W., Lovicu FJ, Ornitz, D.M., and Overbeek P.A. 2001. Patterning the optic neuroepithelium by FGF signaling and Ras activation. Development. 128, 5051-5060.
Saika S, Okada Y, Miyamoto T, Ohnishi Y, Ooshima A, McAvoy JW. Smad translocation and growth suppression in lens epithelial cells by endogenous TGFbeta2 during wound repair. Exp Eye Res. 2001. 72:679-86.
Lovicu FJ, and McAvoy, JW. (2001). FGF-induced lens cell proliferation and differentiation is dependent on MAPK (ERK1/2) signalling. Development. 128. 5075-5084.
Lovicu FJ, Schulz M, Hales AM, Vincent L, Overbeek PA, Chamberlain CG, and McAvoy JW. 2002. TGFß induces the morphological and molecular changes similar to human anterior subcapsular cataract. Brit J Ophthal. 86, 220-226.
Kok A, Lovicu FJ, Chamberlain CG and McAvoy JW. 2002. PDGF influences proliferation and potentiates FGF-induced fibre differentiation in lens epithelial explants. Growth Factors. 20:27-34.
Maruno K, Lovicu FJ , Chamberlain CG and McAvoy JW. 2002. Apoptosis is a feature of TGFß-induced cataract. Clin Exp Optom. 85:76-82.
Bradbury RA, Cropley J, Kifor O, Lovicu FJ, de Iongh RU, Kable E, Brown EM, Seely EW, Peat BB, Conigrave AD. 2002. Localization of the extracellular Ca2+-sensing receptor in the human placenta. Placenta. 2002. 23:192-200.
Saika S, Miyamoto T, Ishida I, Shirai K, Ohnishi Y, Ooshima A, McAvoy JW. TGFbeta-Smad signalling in postoperative human lens epithelial cells. Br J Ophthalmol. 2002. 86:1428-33.
Stump RJW, Ang S, Chen Y, von Bahr T, Lovicu FJ, Pinson K, de Iongh RU, Yamaguchi TP, Sasoon DA, McAvoy JW. (2003) A role for Wnt/ß-catenin signalling in lens epithelial differentiation. Dev Biol. 259:48-61.
Yager M, Hughes JAI, Lovicu FJ, Gunning PW, Weinberger RP, O'Neill, GM. 2003. Functional analysis of the actin-binding protein, tropomyosin 1, in neuroblastoma. Br J Cancer. 89:860-863.
Ang SJ, Stump RJW, Lovicu FJ, McAvoy JW. 2004. Spatial and temporal expression of Wnt and Dickkopf genes during murine lens development. Gene Expression Patterns, 4: 289–295.
Lovicu FJ, Steven P, Saika S,. McAvoy JW. 2004. Aberrant lens fiber differentiation contributes to anterior subcapsular cataract formation in vivo: a process dependent on reduced levels of Pax6. Invest Ophthal Vis Sci. 45:1946-1953.
Thompson J., Lovicu F., Ziman M. 2004.The role of Pax7 in determining the cytoarchitecture of the superior colliculus. Dev Growth Differ. 46:213-218.
Chen Y, Stump RJW, Lovicu FJ, McAvoy JW. 2004. Expression of Frizzleds and secreted frizzled-related proteins (sFRPs) during rodent lens development. Int J Dev Biol. 48:867-877.
Robinson ML, Lovicu FJ. 2004. The Lens: Historical and Comparative Perspectives. In “Development of the Ocular Lens”. Eds. Lovicu FJ and Robinson ML. Cambridge University Press. New York.
Lang RA, McAvoy JW. 2004. Growth factors in lens development. In “Development of the Ocular Lens”. Eds. Lovicu FJ and Robinson ML. Cambridge University Press. New York.
de Iongh RU, Chen Y, Kokkinos MI, McAvoy JW. 2004. BMP and activin receptor expression in lens development. Mol Vis. 10:566-576.
Tanaka T, Saika S, Ohnishi Y, Ooshima A, McAvoy JW, Liu CY, Azhar M, Doetschman T, Kao WW. 2004. Fibroblast growth factor 2: roles of regulation of lens cell proliferation and epithelial-mesenchymal transition in response to injury. Mol Vis. 10:462-7.
Lovicu FJ, Ang S, Chorazyczewska M, McAvoy JW. 2004. Deregulation of Lens Epithelial Cell Proliferation and Differentiation during the Development of TGFß-induced Anterior Subcapsular Cataract. Dev Neurosc 198:(in press).
Lovicu FJ, McAvoy JW. 2004. Growth Factor Regulation Of Lens Development. Dev Biol (in press).